Whereas type 2 diabetes is considered a lifestyle-mediated chronic disease, the importance of environmental risk factors of diabetes is increasingly recognized. Studies indicate that imbalanced homeostasis of certain trace minerals may damage anti-inflammatory and anti-oxidant defense as well as glucose tolerance, which together play pivotal roles in the pathogenesis of diabetes. In addition, studies have linked some heavy metal exposure to the risk of diabetes, though the underlying mechanisms are not completely clear. Despite this, a critical gap remains in the literature on how trace minerals affect diabetes development. Moreover, while an individual trace mineral may be essential for a metabolic pathway, it may interact with other minerals in the metabolism and evolution of diabetes. The advanced techniques profiling metabolite (metabolomics) enable us to measure the full profile of small molecule metabolites circulating in plasma, providing a comprehensive understanding of an individual?s metabolic status that may underlie the associations of trace minerals with diabetes risk. In the proposed project, we will examine trace mineral status in relation to the incidence of diabetes, and insulin resistance; and will identify metabolomic signatures associated with diabetes-related trace mineral patterns in a case-cohort study nested in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. REGARDS is an ongoing US national population-based cohort of 30,239 African American (AA) and Caucasian adults, aged 45 and older at baseline (2003-2007). The proposed case-cohort study will include 1,538 incident diabetes cases and a sub-cohort (n=2,666) randomly sampled within region- race-sex stratum at baseline. This research will help to identify Americans at risk for diabetes and/or metabolic disorders. For minerals that function as nutrients, information generated from this study will be useful for future interventions to maintain a homeostasis of micronutrients with respect to diabetes prevention. For the toxic minerals, at low-to-moderate exposure level, knowledge gained will serve as a scientific foundation for remediation and prevention strategies to reduce the risk of diabetes and other metabolic disorders.